TRH Analogs: In addition to governing the release of thyrotropin and prolactin in the pituitary gland, TRH (L-pyroglutamyl-L-histidyl-L-proline amide) is known to possess a wide variety of effects on both the central nervous system (CNS) and the cardiovascular system (CVS). TRH has shown promise for use in the treatment of shock, as an analeptic and antidepressant, and as a promoter of the regeneration of injured spinal cord. However, the great variety of its biological effects presents a serious drawback to its use as a specific drug. Our early studies with synthetic analogues of TRH (involving modification of the imidazole ring of histidine) has suggested that the peptide hormone elicits each of its physiological responses at a different receptor and that appropriate analogues may achieve some of the desired specificity of action. In contrast to the natural peptide, 4-fluoro-Im-TRH does not bind to rat pituitary cells in vitro and does not release prolactin from them; such results would immediately suggest the analogue to be nonfunctional. When it is microinjected directly into rat brain, however, it effected significant increases in heart rate and blood pressure. We have now prepared and tested by systemic injection a variety of other analogues on the CVS and endocrine systems of conscious rats. 4-TFM-TRH, 2-TFM-TRH and 4-nitro-TRH were as potent as TRH in increasing mean arterial pressure, pulse pressure and heart rate at both 1 mg/kg and 5 mg/kg doses. At the same time, 4-TFM-TRH and 2-TFM-TRH were 4-5 times more potent than TRH in increasing plasma prolactin; 4-nitro-TRH, on the other hand was totally devoid of prolactin-releasing activity. Nor-Val-TRH was as effective as TRH (at either dose) in increasing plasma prolactin but, surprisingly, was devoid of any CVS activity.